Shaping suvorexant: application of experimental and theoretical methods for driving synthetic designs

Dual Orexin Receptor Antagonists (DORA) bind to both the Orexin 1 and 2 receptors. High resolution crystal structures of the Orexin 1 and 2 receptors, both class A GPCRs, were not available at the time of this study, and thus, ligand-based analyses were invoked and successfully applied to the design...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of computer-aided molecular design Vol. 28; no. 1; pp. 5 - 12
Main Authors:	McGaughey, Georgia, Bayly, Christopher I., Cox, Christopher D., Schreier, John D., Breslin, Michael J., Bogusky, Michael, Pitzenberger, Steve, Ball, Richard, Coleman, Paul J.
Format:	Journal Article
Language:	English
Published:	Cham Springer International Publishing 2014 Springer Nature B.V
Subjects:	Animal Anatomy Azepines - chemistry Chemistry Chemistry and Materials Science Computation Computer Applications in Chemistry Crystal structure Crystallography Crystallography, X-Ray Design engineering Histology Humans Ligands Magnetic Resonance Spectroscopy Mathematical analysis Molecular Conformation Molecular Structure Molecules Morphology Orexin Receptor Antagonists Orexin Receptors - chemistry Pharmaceutical sciences Physical Chemistry Receptors Solvation Three dimensional Triazoles - chemistry X-rays Suvorexant ROCS Free energy Conformational analysis
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Dual Orexin Receptor Antagonists (DORA) bind to both the Orexin 1 and 2 receptors. High resolution crystal structures of the Orexin 1 and 2 receptors, both class A GPCRs, were not available at the time of this study, and thus, ligand-based analyses were invoked and successfully applied to the design of DORAs. Computational analysis, ligand based superposition, unbound small-molecule X-ray crystal structures and NMR analysis were utilized to understand the conformational preferences of key DORAs and excellent agreement between these orthogonal approaches was seen in the majority of compounds examined. The predominantly face-to-face (F2F) interaction observed between the distal aromatic rings was the core 3D shape motif in our design principle and was used in the development of compounds. A notable exception, however, was seen between computation and experiment for suvorexant where the molecule exhibits an extended conformation in the unbound small-molecule X-ray structure. Even taking into account solvation effects explicitly in our calculations, we nevertheless find support that the F2F conformation is the bioactive conformation. Using a dominant states approximation for the partition function, we made a comprehensive assessment of the free energies required to adopt both an extended and a F2F conformation of a number of DORAs. Interestingly, we find that only a F2F conformation is consistent with the activities reported.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0920-654X 1573-4951
DOI:	10.1007/s10822-014-9710-x